Optimizing Anticoagulation in Pregnancies With Mechanical Heart Valves

A Prospective Multicenter Cohort Pilot Study Comparing Antithrombotic Regimens in Pregnancies With Mechanical Heart Valves

The purpose of this pilot study is to collect data on pregnancies with mechanical heart valves to see if using a blood thinner called low molecular weight heparin (LMWH) and low dose aspirin (LDA) is comparable to warfarin/vitamin K antagonist (VKA) to reduce the chance of clotting around the mechanical valve and improve survival. The study is a pilot study as the study investigators need to ensure that the blood levels needed for adequate amounts of LMWH and warfarin can be maintained during pregnancy to be able to compare LMWH and aspirin to warfarin. If this study shows that we can collect the tests that are needed for a larger study, the individuals' information who participated in this pilot study will be moved to the larger study. The larger study will compare survival, clot development and cardiac function as well as safety of these two common blood thinners.

Pregnancies with mechanical heart valves (MHVs) have a substantial risk of thromboembolic events, hemorrhage, mortality and low live birth rates. The observational studies that have been published have been challenged by the lack of standardized regimens for antithrombotic agents (including standardized dosing and monitoring), standardized measurements of outcomes, and the observational nature. Notably, there are also limited data collected and described for maternal and neonatal safety and on cardiac morbidity such as left ventricular function (LVF) i.e., left ventricular ejection fraction, frequency of arrhythmias and valve competence after pregnancy. Individuals with MHVs are predominantly from low resource countries and optimizing maternal and fetal morbidity and mortality in these pregnancies should be prioritized similarly as other pregnancies. There is a need for a prospective controlled multicenter study as individual's centers do not have the patient volumes for risk assessment and many centers are in low resource settings. We will conduct a multicenter controlled prospective internal pilot pragmatic study comparing the two standard antithrombotic regimens (LMWH and LDA vs VKAs) for 100 pregnancies with MHVs. The sequential therapy regimen will be combined with the regimen of VKAs as most of the pregnancy is exposed to VKAs, but secondary analysis will be conducted separating the two groups. Patients will be recruited in obstetrical clinics before 12 weeks gestation.

The overall objective is to determine the optimal antithrombotic regimen for pregnancies with MHVs.

3.1 Primary Objective To assess feasibility of conducting a large prospective controlled (adherent to an anticoagulation regimen) study by determining

1) Enrollment rates a) patients enrolled/patients eligible, and b) consent rates (consent obtained/patients approached), 2) Protocol adherence, 3) Ability to accurately collect data and complete the eCRF, 4) Resources required for a larger study and, 5) To ensure accuracy of effect size as described above. 3.2 Secondary Objective(s) To determine the rate of

1. The composite outcome of all-cause maternal mortality (according to gestational age) and mechanical valve thrombosis and the sequelae, arterial embolism leading to organ/limb ischemia;
2. Maternal safety outcomes including A. The frequency of the individual outcomes of the composite outcome B. Cardiac morbidity including arrhythmias requiring electrical or medical cardioversion, cardiac arrest, left ventricular function and valve size following delivery C. Primary postpartum hemorrhage (hemorrhage within 24 hours of delivery and treated by transfusion or requiring critical care or return to surgery) D. Other hemorrhagic events as defined by ISTH criteria (https://bleedingscore.certe.nl/) all at birth and 12 weeks postpartum E. Other maternal adverse events as defined and categorized by MedDRA (https://www.meddra.org/).
3. Pregnancy safety outcomes A. Pregnancy loss at any gestation B. Proportion of preterm delivery (defined as delivery less than 37 weeks gestation) - stratified by spontaneous and iatrogenic preterm delivery, and C. Presence of preeclampsia and degree of severity according to current definitions
4. Fetal/neonatal safety outcomes A. Fetal and neonatal loss defined as miscarriage (fetal loss under 20 weeks of gestation), stillbirth (fetal loss between 20+1 weeks of gestation and birth) and neonatal death (death after birth and within the first 28 days of life).

B. Presence of embryopathy/fetopathy secondary to VKAs C. Small for gestational age neonates less than the 10th percentile for gestational age and D. Need for neonatal critical care.

Inclusion Criteria:

1. Pregnant individuals with one or more MHVs
2. Who consent to participate
3. Are 18 years or older and
4. Less than 12 weeks gestation

Exclusion Criteria:

1. Have a platelet count less than 50 x 10(9)/L as there is an increased risk of bleeding with thrombocytopenia, and/or
2. Have active bleeding defined as bleeding resulting in a hemoglobin reduction ≥10 g/L or in hemodynamic instability.
3. Have new valve thrombosis identified immediately prior to pregnancy